Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism spectrum disorder with an estimated frequency of about 1:4000-5000, affecting all racial and ethnic groups worldwide. Enormous progress in basic and translational FXS research has identified many neuronal targets and allowed early clinical trials of new treatments targeted to the underlying disease. A number of these agents have shown signal for benefit in open-label and early phase trials, but it has been challenging to meet primary behavioral outcomes in larger phase 2b and 3 trials, due to multiple complex issues including dosing age of subjects, length of treatment, placebo effects, and primary outcome off target for drug effect. A significant problem has been poor availability of biomarkers and well-validated cognitive and other objective outcome measures that do not rely on parent report. Further, very long-term treatment over years, a time frame over which placebo controls are not possible, will be necessary to show changes in the trajectory of disease. In order to know whether the disease trajectory has been changed, it will be CRITICAL to have detailed longitudinal phenotyping including cognitive, adaptive, language, motor, behavioral, social, and quality of life on a large cohort of individuals with FXS, in order to define the naturl history of the disease for future comparison in long-term intervention studies. The FORWARD longitudinal database tracks health, behavior and social issues including 3 standardized measures of behavior and social function in a large cohort of individuals with FXS but lacks good consistent cognitive and adaptive data. Given the infrastructure already present, the FORWARD project is the only currently plausible place to collect the necessary detailed longitudinal phenotyping. Thus, through this application, focused on both enhanced measurement and participation, we plan to collaborate with the other Component C FXS clinics to enhance the cohort size in which we will collect a comprehensive core battery of outcome measures yearly for a minimum of 3 years to begin to define the longitudinal trajectory of all aspects of the FXS phenotype (Aim 1). Additionally at our site alone we will collect pilot data longitudinally for two new outcome measures that address two areas of need in the field (Aim 2): objective direct measures of vocal development in infants and toddlers and activity and sleep monitoring in adolescents and adults. Finally, we will implement plans to improve our collection of this data from adults with FXS and from racial and ethnic groups according to the population percentages from our catchment area (Aim 3). Analysis plans for the data collected in this project will be reviewed and modified by experts in FXS outcomes research and CDC partners. Results of analyses resulting from the data collection in this application will be disseminated to all stakeholders including the FXCRC, NFXF, FXS Community Support Network groups, FXS families, other researchers and CDC project partners.